PAPPA's role in female reproduction

This review represents a multispecies summary of the role of pappalysins in female reproductive health. It discusses the potential use of PAPPA and PAPPA2 as biomarkers for oocyte and embryo quality and fetal development.

Pappalysin 1 and 2 (PAPPA and PAPPA2) are metzincin metalloproteinases expressed in the ovaries, endometrium, placenta, and several other organs. These enzymes are responsible for the liberation and regulation of localized bioactive insulin-like growth factors 1 and 2 (IGF1 and IGF2) via the proteolytic cleavage of insulin-like growth factor binding proteins. Several studies have implicated pappalysins as vital components for female fecundity. During the reproductive cycle, PAPPA peaks in dominant ovarian follicles before ovulation due to its response to gonadotropins, increasing follicular IGF availability. In human in vitro fertilization studies, PAPPA has been tested as a biomarker of oocyte and embryo quality. Studies with null mice resulting in offspring with reduced body weight and bone density have demonstrated the requirement of PAPPA for normal fetal development. Evidence supports a role for PAPPA in the establishment and maintenance of viable pregnancies through its influence on endometrial receptivity. Under the influence of PAPPA within the placenta, IGF1 and IGF2 influence mitogenic activity, trophoblastic invasion, and placental development. In addition, PAPPA has been proposed as a biomarker to identify aneuploidies in utero as well as a biomarker to recognize ectopic pregnancies. This narrative review examines PAPPA and PAPPA2 expression and localization, regulation, and function in the female reproductive tract in multiple species. Furthermore, it examines the role of PAPPA and PAPPA2 preceding and throughout pregnancy and as a molecular marker of oocyte maturation, embryo quality and development.